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Crystalline salts of 7-′4-(4-fluorophenyl) -6-isopropyl-2-′methyl (methylsulfonyl) amino!pyrimidin-5-yl!- (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid

Inactive Publication Date: 2006-10-31
ASTRAZENECA AB +1
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  • Abstract
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AI Technical Summary

Problems solved by technology

A powdery or amorphous form of a compound intended for pharmaceutical use may give rise to manufacturing problems and there is therefore a need to identify alternative salts of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid which are crystalline.
A difficulty is also experienced in obtaining pure amorphous calcium salt using the procedure disclosed in EPA 521471, because of the difficulty in purification of the precursor sodium salt arising from its physical form.

Method used

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  • Crystalline salts of 7-′4-(4-fluorophenyl) -6-isopropyl-2-′methyl (methylsulfonyl) amino!pyrimidin-5-yl!- (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid
  • Crystalline salts of 7-′4-(4-fluorophenyl) -6-isopropyl-2-′methyl (methylsulfonyl) amino!pyrimidin-5-yl!- (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid
  • Crystalline salts of 7-′4-(4-fluorophenyl) -6-isopropyl-2-′methyl (methylsulfonyl) amino!pyrimidin-5-yl!- (3R, 5S) -3, 5-dihydroxyhept-6-enoic acid

Examples

Experimental program
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Effect test

example 1

[0040]A solution of methylamine in methanol (1.4 ml of a 40% solution) was added with stirring to a solution of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid (obtained as described below) at −5° C. The mixture was stirred at 30° C. for 90 minutes and then cooled to 3° C. The crystalline product was collected by filtration, washed with acetonitrile and dried under vacuum at 40° C. to give methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (3.85 g; 87.9% yield) as white crystals. (The same crystalline salt was obtained when a 40% solution of methylamine in water (1.1 ml) was used). The X-ray powder diffraction spectra (XRD) for a typical sample of the crystalline methylammonium salt is shown in FIG. 2 hereinafter. The ten most prominent peaks in the XRD occur at about 2-theta=8.2, 12.3, 15.7, 16.5, 17.6, 18.7, 19.9, 21.0, 24....

example 2

[0048]Methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (10 g) was added to acetonitrile (125 ml) and water (5 ml). The mixture was cooled to 5° C. and the pH adjusted to 3.7 with 1M hydrochloric acid in saturated brine (19 ml). The aqueous phase was separated off and the resulting solution was dried over anhydrous magnesium sulphate. Tris(hydroxymethyl)aminomethane (2.48 g) was added and the solution was allowed to warm to ambient temperature and stirred for 2 hours. The crystalline product was isolated by filtration at ambient temperature and dried at 30° C. under vacuum to give crystalline tris(hydroxymethyl)methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate as white crystals. The X-ray powder diffraction spectra for a typical sample of the crystalline tris(hydroxymethyl)methylammonium salt is shown in FIG. 5 her...

example 3

[0049]Methylammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (10 g) was added to ethyl acetate (125 ml) and water (30 ml). The mixture was cooled to 5° C. and 2M hydrochloric acid (9.5 ml) was added to obtain a two-phase solution. The aqueous phase was separated off and the organic phase was washed with water (30 ml) and dried over anhydrous magnesium sulphate. A solution of diethanolamine (3.1 ml) in ethyl acetate (5 ml) was added and the solution was allowed to warm to ambient temperature. The product was isolated by filtration at 0° C. to 5° C. and dried at 30° C. under vacuum to give diethanolammonium (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoate (8.0 g) as white crystals. The X-ray powder diffraction spectra for a typical sample of the crystalline diethanolammonium salt is shown in FIG. 4 hereinafter. The ten most prominent p...

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Abstract

The invention relates to crystalline salts of the compound (E)-7-[4-(4-fluorophenyl)isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid of formula (I), as well as processes for their manufacture, pharmaceutical compositions containing them, and their uses

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This is a continuation of application Ser. No. 10 / 203,890, filed Aug. 15, 2002, now U.S. Pat. No. 6,841,554, which is a PCT National Stage of PCT / GB01 / 00574 filed Feb. 12, 2001, which claims priority to GB 0003305.0 filed Feb. 15, 2000.BACKGROUND OF THE INVENTION[0002]The present invention relates to pyrimidine derivatives, and more particularly to novel crystalline salts of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid of the formula[0003]which are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and as intermediates in the manufacture of, for example, the non-crystalline calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimnidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid of the formula[0004][0005]The invention also concerns pharmaceutical compositions which include the...

Claims

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Application Information

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IPC IPC(8): C07D239/42A61K31/505A61P3/06A61P9/10A61P43/00
CPCC07D239/42A61P3/00A61P3/06A61P43/00A61P9/00A61P9/10
Inventor TAYLOR, NIGEL PHILIPOKADA, TETSUO
Owner ASTRAZENECA AB
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